In vitro investigations into the roles of CYP450 enzymes and drug transporters in the drug interactions of zanubrutinib, a covalent Bruton's tyrosine kinase inhibitor

Autor: Lai Wang, Heather Zhang, Srikumar Sahasranaman, Ying C. Ou, Dan Su, Zhiyu Tang, Fan Wang
Rok vydání: 2021
Předmět:
Zdroj: Pharmacology Research & Perspectives, Vol 9, Iss 6, Pp n/a-n/a (2021)
Pharmacology Research & Perspectives
ISSN: 2052-1707
DOI: 10.1002/prp2.870
Popis: Zanubrutinib is a highly selective, potent, orally available, targeted covalent inhibitor (TCI) of Bruton's tyrosine kinase (BTK). This work investigated the in vitro drug metabolism and transport of zanubrutinib, and its potential for clinical drug–drug interactions (DDIs). Phenotyping studies indicated cytochrome P450 (CYP) 3A are the major CYP isoform responsible for zanubrutinib metabolism, which was confirmed by a clinical DDI study with itraconazole and rifampin. Zanubrutinib showed mild reversible inhibition with half maximal inhibitory concentration (IC50) of 4.03, 5.69, and 7.80 μM for CYP2C8, CYP2C9, and CYP2C19, respectively. Data in human hepatocytes disclosed induction potential for CYP3A4, CYP2B6, and CYP2C enzymes. Transport assays demonstrated that zanubrutinib is not a substrate of human breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)2, or organic anion transporter (OAT)1/3 but is a potential substrate of the efflux transporter P‐glycoprotein (P‐gp). Additionally, zanubrutinib is neither an inhibitor of P‐gp at concentrations up to 10.0 μM nor an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, and OAT3 at concentrations up to 5.0 μM. The in vitro results with CYPs and transporters were correlated with the available clinical DDIs using basic models and mechanistic static models. Zanubrutinib is not likely to be involved in transporter‐mediated DDIs. CYP3A inhibitors and inducers may impact systemic exposure of zanubrutinib. Dose adjustments may be warranted depending on the potency of CYP3A modulators.
This study evaluates the in vitro metabolism and drug–drug interaction (DDI) potential of zanubrutinib through interaction with CYP450s and transporters. CYP450 phenotyping using recombinant CYP enzymes and other studies identified CYP3A as the major enzyme responsible for the metabolism of zanubrutinib, which leads to its major DDIs when co‐administered with CYP3A modulators.
Databáze: OpenAIRE
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